sirolimus and aurapten

Matrix metalloproteinase (MMP)-7 is considered to play essential roles in cancer progression. We examined the efficacy of auraptene, a citrus coumarin derivative, for suppressing MMP-7 expression in the human colorectal adenocarcinoma cell line HT-29. Auraptene remarkably inhibited the production of proMMP-7 protein, without affecting its mRNA expression level. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), showed similar results, suggesting that auraptene suppresses mTOR-dependent proMMP-7 translation. Interestingly, however, auraptene showed no effects on the activation of Akt/mTOR signaling, whereas the phosphorylation levels of 4E binding protein (4EBP)1 and eukaryotic translation initiation factor (eIF)4B were substantially decreased. In addition, auraptene remarkably dephosphorylated constitutively activated extracellular signal-regulated kinase (ERK)1/2. Transfection of ERK1/2 siRNA led to a significant reduction of proMMP-7 protein production as well as of the phosphorylation of eIF4B. These results demonstrate that auraptene targets the translation step for proMMP-7 protein synthesis by disrupting ERK1/2-mediated phosphorylation of 4EBP1 and eIF4B.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Citrus; Coumarins; Enzyme Precursors; Eukaryotic Initiation Factors; Humans; MAP Kinase Signaling System; Metalloendopeptidases; Neoplasm Proteins; Phosphorylation; Protein Biosynthesis; Protein Kinases; Protein Processing, Post-Translational; RNA, Messenger; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Transfection